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Abstract Using e + e − annihilation data corresponding to a total integrated luminosity of 6.32 fb −1 collected at the center-of-mass energies between 4.178 and 4.226 GeV with the BESIII detector, we perform an amplitude analysis of the decay D s + $$ {D}_s^{+} $$ → K − K + π + π + π − and determine the relative fractions and phases of different intermediate processes. Absolute branching fraction of D s + $$ {D}_s^{+} $$ → K − K + π + π + π − decay is measured to be (6.60 ± 0.47stat. ± 0.38syst. ) × 10 −3. The dominant intermediate process is D s + $$ {D}_s^{+} $$ → a 1(1260)+ ϕ, ϕ → K − K + , a 1(1260)+ → ρπ + , ρ → π + π − , with a branching fraction of (5.15 ± 0.41stat. ± 0.32syst. ) × 10 −3.

Abstract Using data collected with the BESIII detector in e + e − collisions at center-of-mass energies between 4.178 and 4.226 GeV and corresponding to 6.32 fb −1 of integrated luminosity, we report the amplitude analysis and branching-fraction measurement of the D s + $$ {D}_s^{+} $$ → π + π 0 η′ decay. We find that the dominant intermediate process is D s + $$ {D}_s^{+} $$ → ρ + η′ and the significances of other resonant and nonresonant processes are all less than 3σ. The upper limits on the branching fractions of S-wave and P-wave nonresonant components are set to 0.10% and 0.74% at the 90% confidence level, respectively. In addition, the branching fraction of the D s + $$ {D}_s^{+} $$ → π + π 0 η′ decay is measured to be (6.15 ± 0.25(stat.) ± 0.18(syst.))%, which receives significant contribution only from D s + $$ {D}_s^{+} $$ → ρ + η′ according to the amplitude analysis.

Abstract Using a data set corresponding to an integrated luminosity of 6.32 fb −1 recorded by the BESIII detector at center-of-mass energies between 4.178 and 4.226 GeV, an amplitude analysis of the decay D s + $$ {D}_s^{+} $$ → π + π 0 π 0 is performed, and the relative fractions and phases of different intermediate processes are determined. The absolute branching fraction of the decay D s + $$ {D}_s^{+} $$ → π + π 0 π 0 is measured to be (0.50 ± 0.04stat ± 0.02syst)%. The absolute branching fraction of the intermediate process D s + $$ {D}_s^{+} $$ → f 0(980)π + , f 0(980) → π 0 π 0 is determined to be (0.28 ± 0.04stat ± 0.04syst)%.

The Born cross sections of e+e−→Σ0Σ¯0 are measured at center-of-mass energies from 2.3864 to 3.0200 GeV using data samples with an integrated luminosity of 328.5 pb−1 collected with the BESIII detector operating at the BEPCII collider. The analysis makes use of a novel reconstruction method for energies near production threshold, while a single-tag method is employed at other center-of-mass energies. The measured cross sections are consistent with earlier results from BaBar, with a substantially improved precision. The cross-section lineshape can be well described by a perturbative QCD-driven energy function. In addition, the effective form factors of the Σ0 baryon are determined. The results provide precise experimental input for testing various theoretical predictions.

Gamma alumina (γ-Al2O3) is widely used as a catalyst and catalytic support due to its high specific surface area and porosity. However, synthesis of γ-Al2O3 nanocrystals is often a complicated process requiring high temperatures or additional post-synthetic steps. Here, we report a single-step synthesis of size-controlled and monodisperse, facetted γ-Al2O3 nanocrystals in an inductively coupled nonthermal plasma reactor using trimethylaluminum and oxygen as precursors. Under optimized conditions, we observed phase-pure, cuboctahedral γ-Al2O3 nanocrystals with defined surface facets. Nuclear magnetic resonance studies revealed that nanocrystal surfaces are populated with AlO6, AlO5 and AlO4 units with clusters of hydroxyl groups. Nanocrystal size tuning was achieved by varying the total reactor pressure yielding particles as small as 3.5 nm, below the predicted thermodynamic stability limit for γ-Al2O3.

Sulfur/carbon copolymers have emerged as promising alternatives for conventional crystalline sulfur cathodes for lithium-sulfur batteries. Among these, sulfur-n-1,3-diisopropenylbenzene (S/DIB) copolymers, which present a 3D network of DIB molecules interconnected via sulfur chains, have particularly shown a good performance and, therefore, have been under intensive experimental and theoretical investigations. However, their structural complexity and flexibility have hindered a clear understanding of their structural evolution during redox reactions at an atomistic level. Here, by performing state-of-the-art ab initio molecular dynamics-based Raman spectroscopy simulations, we investigate the spectral fingerprints of S/DIB copolymers arising from local structures during consecutive reactions with lithium. We discuss in detail Raman spectral changes in particular frequency ranges which are common in S/DIB copolymers having short sulfur chains and those consisting of longer ones. We also highlight those distinctive spectroscopic fingerprints specific to local S/DIB structures containing only short or long sulfur chains. This distinction could serve to help distinguish between them experimentally during discharge. Our theoretically predicted results are in a good agreement with experimental Raman measurements on coin cells at different discharge stages. This work represents, for the first time, an attempt to compute Raman fingerprints of sulfur/carbon copolymer cathodes during battery operation including quantum-chemical and finite-temperature effects, and provides a guideline for Raman spectral changes of arbitrary electrodes during discharge., (© 2024 The Authors. ChemPhysChem published by Wiley-VCH GmbH.)

Background: Primary optic nerve sheath meningiomas (ONSMs) represent a group of benign tumors originating from the optic nerve sheath, typically causing painless, gradual onset monocular visual loss, which can result in blindness if left untreated. Radiation therapy represents an important treatment option for patients with ONSM, allowing for preservation and potential improvement in visual function. In particular, proton radiotherapy may enable a reduction of the side effects due to its physical advantage of an inverted dose profile with a steep dose gradient. The study investigates the visual acuity, local tumor control, and treatment-related toxicities following proton beam radiotherapy with a single institutional cohort comprising 32 patients treated for ONSM., Methods: Patients with primary ONSM, either histologically (16/32) or radiologically confirmed (16/32), which were treated at the Department of Radiation Oncology at the University Hospital Heidelberg (Germany) were assessed in regard to their visual outcomes, treatment toxicity, and local tumor control following radiotherapy according to response assessment in neuro-oncology criteria., Results: After a median follow-up time of 39.5 months, the 5-year local progression-free survival was estimated at 100%, with 84.4% of patients reporting improvement or stability in visual acuity during their last follow-up. Radiation-induced optic neuropathy (RION) was encountered in 9.4%., Conclusions: Our study demonstrates proton beam therapy as a safe and effective treatment alternative in the therapeutic management of ONSMs. RION represents a rare but dreaded complication after treatment. Future head-to-head comparisons with photon radiotherapy in a prospective setting are required to demonstrate a potential, additional clinical benefit., Competing Interests: P.H.S. received honoraria from Novocure for participation in the Advisory Board. A.v.D. has licenses and patents for the VE1 (Roche Ventana) and H09 (Dianova) antibodies, and patent pending for the methylation-based tumor classification. F.S. and A.v.D. are the founders and shareholders of Heidelberg Epignostix GmbH. J.D. received honorary from RaySearch Laboratories, Vision RT Limited, Merck Serono, Siemens Healthcare, PTW-Freiburg Dr. Pychlau, and Accuray Incorporated. S.M.K. is a consultant for Brainlab (Munich), Ulrich Medical (Ulm) and Need Inc. (Santa Monica), and shareholder of Need Inc. (Santa Monica), and received travel funding from Nextim Pic (Helsinki). J.D. is the CEO of the Heidelberg Ion Beam Therapy Center (HIT), and a member of the Board of Directors at the Heidelberg University Hospital., (© The Author(s) 2024. Published by Oxford University Press, the Society for Neuro-Oncology and the European Association of Neuro-Oncology.)

Local recurrence after radiotherapy is common in locally advanced head and neck cancer (HNC) patients. Re-irradiation can improve local disease control, but disease progression remains frequent. Hence, predictive biomarkers are needed to adapt treatment intensity to the patient's individual risk. We quantified circulating tumor DNA (ctDNA) in sequential plasma samples and correlated ctDNA levels with disease outcome. Ninety four longitudinal plasma samples from 16 locally advanced HNC patients and 57 healthy donors were collected at re-radiotherapy baseline, after 5 and 10 radiation fractions, at irradiation end, and at routine follow-up visits. Plasma DNA was subjected to low coverage whole genome sequencing for copy number variation (CNV) profiling to quantify ctDNA burden. CNV-based ctDNA burden was detected in 8/16 patients and 25/94 plasma samples. Ten additional ctDNA-positive samples were identified by tracking patient-specific CNVs found in earlier sequential plasma samples. ctDNA-positivity after 5 and 10 radiation fractions (both: log-rank, p = .050) as well as at the end of irradiation correlated with short progression-free survival (log-rank, p = .006). Moreover, a pronounced decrease of ctDNA toward re-radiotherapy termination was associated with worse treatment outcome (log-rank, p = .005). Dynamic ctDNA tracking in serial plasma beyond re-radiotherapy reflected treatment response and imminent disease progression. In five patients, molecular progression was detected prior to tumor progression based on clinical imaging. Our findings emphasize that quantifying ctDNA during re-radiotherapy may contribute to disease monitoring and personalization of adjuvant treatment, follow-up intervals, and dose prescription., (© 2024 The Author(s). International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)

Helium ion therapy (HRT) is a promising modality for the treatment of pediatric tumors and those located close to critical structures due to the favorable biophysical properties of helium ions. This in silico study aimed to explore the potential benefits of HRT in advanced juvenile nasopharyngeal angiofibroma (JNA) compared to proton therapy (PRT). We assessed 11 consecutive patients previously treated with PRT for JNA in a definitive or postoperative setting with a relative biological effectiveness (RBE) weighted dose of 45 Gy (RBE) in 25 fractions at the Heidelberg Ion-Beam Therapy Center. HRT plans were designed retrospectively for dosimetric comparisons and risk assessments of radiation-induced complications. HRT led to enhanced target coverage in all patients, along with sparing of critical organs at risk, including a reduction in the brain integral dose by approximately 27%. In terms of estimated risks of radiation-induced complications, HRT led to a reduction in ocular toxicity, cataract development, xerostomia, tinnitus, alopecia and delayed recall. Similarly, HRT led to reduced estimated risks of radiation-induced secondary neoplasms, with a mean excess absolute risk reduction of approximately 30% for secondary CNS malignancies. HRT is a promising modality for advanced JNA, with the potential for enhanced sparing of healthy tissue and thus reduced radiation-induced acute and long-term complications.

Objectives: Surgical resection is a key component of the treatment of head and neck cancer and the achievement of free surgical margins are essential for the patients' outcome in terms of survival. While there is a general recommendation for a free resection range of 5 mm, up to date, there is a lack of investigations on the quality of tumor resection in dependence of affected subsite and tumor stage. In the presented study, predictors for the achieved resection margins in surgically treated oral squamous cell carcinomas were analyzed., Materials and Methods: A cohort of 567 patients was included in a retrospective analysis and resection status with exact margin ranges were analysed. Tumor stage, affected subsite and the results of the intraoperative frozen section analysis were assessed. Primary endpoint was the achieved resection margin in mm, secondary endpoints were overall and progression-free survival., Results: The observed mean values of minimal resection margins differed significantly between the investigated subsites (p = 0.042),pathological tumor stages (p < 0.001) and in tumors which demonstrated perineural infiltration (Pn1, p = 0.002). Furthermore, there was a significant impact of the results of the intraoperative frozen section analysis on progression-free and overall survival (p < 0.001)., Conclusions: Our data clearly indicate that resection status differs between tumors of different subsites and tumor stages., Clinical Relevance: Clinical procedures should be adapted in order to achieve similar certainty in all resections, and, thus to improve patients' outcome., (© 2024. The Author(s).)

Background: While surgical resection remains the primary treatment approach for symptomatic or growing meningiomas, radiotherapy represents an auspicious alternative in patients with meningiomas not safely amenable to surgery. Biopsies are often omitted in light of potential postoperative neurological deficits, resulting in a lack of histological grading and (molecular) risk stratification. In this prospective explorative biomarker study, extracellular vesicles in the bloodstream will be investigated in patients with macroscopic meningiomas to identify a biomarker for molecular risk stratification and disease monitoring., Methods: In total, 60 patients with meningiomas and an indication of radiotherapy (RT) and macroscopic tumor on the planning MRI will be enrolled. Blood samples will be obtained before the start, during, and after radiotherapy, as well as during clinical follow-up every 6 months. Extracellular vesicles will be isolated from the blood samples, quantified and correlated with the clinical treatment response or progression. Further, nanopore sequencing-based DNA methylation profiles of plasma EV-DNA will be generated for methylation-based meningioma classification., Discussion: This study will explore the dynamic of plasma EVs in meningioma patients under/after radiotherapy, with the objective of identifying potential biomarkers of (early) tumor progression. DNA methylation profiling of plasma EVs in meningioma patients may enable molecular risk stratification, facilitating a molecularly-guided target volume delineation and adjusted dose prescription during RT treatment planning., (© 2024. The Author(s).)

Motivation is central for successful learning processes and lifelong learning. In the present study, the motivational development of vocational students in a learning environment promoting self-regulated learning (SRL) was examined in comparison to a control group with regular, teacher-centered instruction. The first aim was to examine the development of the dispositional and situational motivation of vocational students. The second aim was to gain a deeper understanding of the students' motivational experiences and the factors of the learning environment that promote and impede motivation. For this purpose, a mixed-methods design was applied. Through multilevel analysis, we investigated the development of dispositional motivation between the beginning and the end of the first year of vocational education ( N  = 159), as well as the development of situational motivation over the first 14 weeks using weekly motivation measures ( N  = 119). In addition, we interviewed 19 students from the SRL-promoting and regular school settings. The quantitative results revealed significant changes in dispositional and situational motivation over time. The qualitative results showed that the three basic psychological needs (relatedness, competence, and autonomy) were central determinants of the students' motivation in both learning environments-albeit to varying extents. Overall, the SRL-promoting learning environment has positive effects on student motivation, but interindividual differences must be considered. Moreover, the results shed light on the coexistence of different motivation regulations within students and interindividual differences in the interpretation of the satisfaction of the three basic psychological needs., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors.)

Purpose: Radiation treatment of sinonasal malignancies is a challenging task due to proximity to critical structures of the head and neck and skull base. Local tumor control is highly dose-dependent, but dose application is limited due to accompanying toxicity and dose constraints. To evaluate the toxicity and efficacy of combined radiation treatment with intensity-modulated radiation therapy (IMRT) and carbon ion boost, we conducted a prospective phase 2 IMRT-Heidelberg Ion-Beam Therapy Sinonasal Tumors (HIT-SNT) trial., Methods and Materials: Between 2011 and 2019, we treated 35 patients with histologically proven, incompletely resected or inoperable adeno- (51%) or squamous cell carcinoma (49%) of the paranasal sinuses with combined IMRT (50 Gy) and carbon ion boost (24 Gy relative biologic effectiveness) to a total dose of 74 Gy., Results: Acute mucositis Common Terminology Criteria for Adverse Events (CTCAE) grade 3 occurred in 12% of patients (n = 4) and was accompanied by odynophagia CTCAE grade 3. Except for 1 case of grade 3 weight loss, no other acute high-grade toxicity (grade 3-4) was observed. In a small patient cohort of 15 patients eligible for long-term follow-up we have seen no high-grade (grade ≥3) long-term side effects 2 years after radiation therapy. None of these patients suffered from therapy-associated vision or hearing loss. Secondary endpoints were 2-year overall survival, 2-year local progression-free survival, 2-year progression-free survival, and 2-year metastases-free survival with 79.4%, 61.8%, 61.8%, and 64.8%, respectively., Conclusions: To our knowledge, this is the first prospective data on toxicity and outcome of bimodal radiation therapy for the rare entity of sinonasal malignancies. Our study shows a low rate of CTCAE-reported acute toxicity with reasonable tumor control and survival rates after bimodal radiation therapy, which therefore remains a therapy approach to be further evaluated., (Copyright © 2023. Published by Elsevier Inc.)

Introduction: Postoperative radiotherapy can improve locoregional control (LC) in oral cavity squamous cell carcinoma (OCSCC) patients with positive resection margins. The present study aimed to evaluate the impact of surgical margin size on LC in this patient population., Methods: This retrospective study involved 162 patients with OCSCC who underwent postoperative radiotherapy between 2000 and 2020 at the Department of Radiation Oncology, University Hospital Heidelberg and the German Cancer Research Center. The study aimed to determine the impact of different resection margins on LC, as well as overall survival (OS), progression-free survival (PFS), and treatment-related toxicity (CTCAE 4.03)., Results: Seventy-seven patients (47.5%) had involved (<1 mm) margins, 22 patients (13.6%) close (≤5 mm) margins, and 63 patients (38.9%) clear (>5 mm) margins. A surgical margin ≤ 5 mm was a significant predictor for worse LC (HR 2.6, 95% CI 1.2, 6.1), but not for OS (HR 1.2, CI 0.7, 1.9) or PFS (HR 1.2, 0.7, 2.0)., Conclusion: Patients who have narrow resection margins (1-5 mm) experience poor local control and should receive postoperative radiotherapy. It is necessary to conduct further prospective studies to determine whether a narrower margin window could be achieved to better determine the appropriate indication for adjuvant radiotherapy., Competing Interests: Declaration of Conflicting InterestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Purpose: To provide the first report on proton radiotherapy (PRT) in the management of advanced nasopharyngeal angiofibroma (JNA) and evaluate potential benefits compared to conformal photon therapy (XRT)., Methods: We retrospectively reviewed 10 consecutive patients undergoing PRT for advanced JNA in a definitive or postoperative setting with a relative biological effectiveness weighted dose of 45 Gy in 25 fractions between 2012 and 2022 at the Heidelberg Ion Beam Therapy Center. Furthermore, dosimetric comparisons and risk estimations for short- and long-term radiation-induced complications between PRT plans and helical XRT plans were conducted., Results: PRT was well tolerated, with only low-grade acute toxicities (CTCAE I-II) being reported. The local control rate was 100% after a median follow-up of 27.0 (interquartile range 13.3-58.0) months. PRT resulted in considerable tumor shrinkage, leading to complete remission in five patients and bearing the potential to provide partial or complete symptom relief. Favorable dosimetric outcomes in critical brain substructures by the use of PRT translated into reduced estimated risks for neurocognitive impairment and radiation-induced CNS malignancies compared to XRT., Conclusions: PRT is an effective treatment option for advanced JNA with minimal acute morbidity and the potential for reduced radiation-induced long-term complications.

There is high agreement that motivation is an important factor for successful learning processes and outcomes. But how do students differ in terms of motivation and how do these differences affect the effectiveness of a motivation intervention? As an intervention interacts with students' characteristics, students' heterogeneity must be considered and homogeneous intervention effects must be critically examined. This study aimed to identify motivation profiles of a specifically vulnerable student group, namely students in the lowest ability tier in the learning of mathematics. Within the framework of self-determination theory, we investigated how these profiles changed during Grade 7 and Grade 8. Furthermore, the study examined whether a particular intervention setting aimed at promoting positive emotions and motivation in learning had an impact on the patterns of change in the specific motivation profiles compared to students in the control condition. A latent profile analysis based on self-reported intrinsic, identified, introjected, and external regulation of 348 students revealed three motivation profiles, consisting of (a) low-mixed, (b) high-mixed, and (c) self-determined. Results of the latent transition analysis indicated that the majority of students tended to remain in the same profile and also revealed different effects of the intervention on different motivation profiles. The intervention seemed to be better tailored to students in the low-mixed motivation profile than to students in other profiles. This result highlights the nature of differential effects between students., Competing Interests: Declaration of Competing Interest None., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

The aim of this study was to analyze the clinical outcomes of three types of minor salivary gland carcinomas (adenoid-cystic carcinomas (ACC), adeno carcinomas not otherwise specified (AC-NOS), and mucoepidermoid carcinomas (MEC)) after primary surgical therapy. A retrospective cohort study was designed and patients with cancer of the minor oral salivary glands treated in our department in the years 2011 to 2022 were included. Clinicopathological data were evaluated to compare overall survival and progression-free survival between the entities. Eighty-one patients were included. The rates of cervical metastases were 38.9% for ACC, 25% for MEC, and 9.1% for AC-NOS. ACC exhibited significantly higher rates of local and systemic disease recurrence ( p = 0.02), and the presence of neck node metastases was confirmed as an independent prognostic factor for progression-free survival ( p = 0.014). Treatment success in terms of oncological outcome varied significantly between the different entities and implies different treatment regimens for each tumor entity.

Introduction: Re-irradiation is frequently performed in the era of precision oncology, but previous doses to organs-at-risk (OAR) must be assessed to avoid cumulative overdoses. Stereotactic magnetic resonance-guided online adaptive radiotherapy (SMART) enables highly precise ablation of tumors close to OAR. However, OAR doses may change considerably during adaptive treatment, which complicates potential re-irradiation. We aimed to compare the baseline plan with different dose accumulation techniques to inform re-irradiation., Patients & Methods: We analyzed 18 patients who received SMART to lung or liver tumors inside prospective databases. Cumulative doses were calculated inside the planning target volumes (PTV) and OAR for the adapted plans and theoretical non-adapted plans via (1) cumulative dose volume histograms (DVH sum plan) and (2) deformable image registration (DIR)-based dose accumulation to planning images (DIR sum plan). We compared cumulative dose parameters between the baseline plan, DVH sum plan and DIR sum plan using equivalent doses in 2 Gy fractions (EQD2)., Results: Individual patients presented relevant increases of near-maximum doses inside the proximal bronchial tree, spinal cord, heart and gastrointestinal OAR when comparing adaptive treatment to the baseline plans. The spinal cord near-maximum doses were significantly increased in the liver patients (D2% median: baseline 6.1 Gy, DIR sum 8.1 Gy, DVH sum 8.4 Gy, p = 0.04; D0.1 cm³ median: baseline 6.1 Gy, DIR sum 8.1 Gy, DVH sum 8.5 Gy, p = 0.04). Three OAR overdoses occurred during adaptive treatment (DIR sum: 1, DVH sum: 2), and four more intense OAR overdoses would have occurred during non-adaptive treatment (DIR sum: 4, DVH sum: 3). Adaptive treatment maintained similar PTV coverages to the baseline plans, while non-adaptive treatment yielded significantly worse PTV coverages in the lung (D95% median: baseline 86.4 Gy, DIR sum 82.4 Gy, DVH sum 82.2 Gy, p = 0.006) and liver patients (D95% median: baseline 87.4 Gy, DIR sum 82.1 Gy, DVH sum 81.1 Gy, p = 0.04)., Conclusion: OAR doses can increase during SMART, so that re-irradiation should be planned based on dose accumulations of the adapted plans instead of the baseline plan. Cumulative dose volume histograms represent a simple and conservative dose accumulation strategy., (© 2023. The Author(s).)

Background: The current World Health Organization (WHO) classification of brain tumors distinguishes 3 malignancy grades in meningiomas, with increasing risk of recurrence from CNS WHO grades 1 to 3. Radiotherapy is recommended by current EANO guidelines for patients not safely amenable to surgery or after incomplete resection in higher grades. Despite adequately predicting recurrence probability for the majority of CNS WHO grade 2 meningioma patients, a considerable subset of patients demonstrates an unexpectedly early tumor recurrence following radiotherapy., Methods: A retrospective cohort of 44 patients with CNS WHO grade 2 meningiomas were stratified into 3 risk groups ( low , intermediate , and high ) using an integrated morphological, CNV- and methylation family-based classification. Local progression-free survival (lPFS) following radiotherapy (RT) was analyzed and total dose of radiation was correlated with survival outcome. Radiotherapy treatment plans were correlated with follow-up images to characterize the pattern of relapse. Treatment toxicities were further assessed., Results: Risk stratification of CNS WHO grade 2 meningioma into integrated risk groups demonstrated a significant difference in 3-year lPFS following radiotherapy between the molecular low- and high -risk groups. Recurrence pattern analysis revealed that 87.5 % of initial relapses occurred within the RT planning target volume or resection cavity., Conclusions: Integrated risk scoring can identify CNS WHO grade 2 meningioma patients at risk or relapse and dissemination following radiotherapy. Therapeutic management of CNS WHO grade 2 meningiomas and future clinical trials should be adjusted according to the molecular risk-groups, and not rely on conventional CNS WHO grading alone., Competing Interests: The authors declare no conflicts of interest., (© The Author(s) 2023. Published by Oxford University Press, the Society for Neuro-Oncology and the European Association of Neuro-Oncology.)

Background: Stereotactic radiotherapy of ultracentral lung tumors (ULT) is challenging as it may cause overdoses to sensitive mediastinal organs with severe complications. We aimed to describe long-term outcomes after stereotactic magnetic resonance (MR)-guided online adaptive radiotherapy (SMART) as an innovative treatment of ULT., Patients & Methods: We analyzed 36 patients that received SMART to 40 tumors between 02/2020 - 08/2021 inside prospective databases. ULT were defined by planning target volume (PTV) overlap with the proximal bronchial tree or esophagus. We calculated Kaplan Meier estimates for overall survival (OS) and progression-free survival (PFS), and competing risk estimates for the incidence of tumor progression and treatment-related toxicities. ULT patients (N = 16) were compared to non-ULT patients (N = 20)., Results: Baseline characteristics were similar between ULT and non-ULT, but ULT were larger (median PTV: ULT 54.7 cm 3 , non-ULT 19.2 cm 3 ). Median follow-up was 23.6 months. ULT and non-ULT showed a similar OS (2-years: ULT 67%, non-ULT 60%, p = 0.7) and PFS (2-years: ULT 37%, non-ULT 34%, p = 0.73). Progressions occurred mainly at distant sites (2-year incidence of distant progression: ULT 63%, non-ULT 61%, p = 0.77), while local tumor control was favorable (2-year incidence of local progression: ULT 7%, non-ULT 0%, p = 0.22). Treatment of ULT led to significantly more toxicities ≥ grade (G) 2 (ULT: 9 (56%), non-ULT: 1 (5%), p = 0.002). Most toxicities were moderate (G2). Two ULT patients developed high-grade toxicities: 1) esophagitis G3 and bronchial bleeding G4 after VEGF treatment, 2) bronchial bleeding G3. Estimated incidence of high-grade toxicities was 19% (3-48%) in ULT, and no treatment-related death occurred., Conclusion: Our small series supports SMART as potentially effective treatment of ULT. SMART with careful fractionation could reduce severe complications, but treatment of ULT remains a high-risk procedure and needs careful benefit-risk-assessment., Competing Interests: Disclosures J. H.-R. and S. K. received speaker fees from ViewRay Inc. J. H.-R. received speaker fees from Pfizer Inc., travel reimbursement from ViewRay Inc., IntraOP Medical and Elekta Instrument AB as well as grants from IntraOP Medical and Varian Medical Systems outside the submitted work. S.A. and J.D. received grants from Accuray International Sàrl and Merck Serono GmbH outside the submitted work. J.D. received grants from CRI – The Clinical Research Institute GmbH, View Ray Inc., Accuray Incorporated, RaySearch Laboratories AB, Vision RT limited, Astellas Pharma GmbH, Astra Zeneca GmbH, Solution Akademie GmbH, Ergomed PLC Surrey Research Park, Siemens Healthcare GmbH, Quintiles GmbH, Pharmaceutecal Research Associates GmbH, Boehringer Ingelheim Pharma GmbH Co, PTW-Freiburg Dr. Pychlau GmbH, Nanobiotix A.A. and IntraOP Medical outside the submitted work. M.T. received speaker fees, advisory board honoraria and travel reimbursements from Abbvie, Bristol-Myers Squibb, MSD, Astrazeneca, Novartis, Roche, Takeda, Lilly, Chugai, Celgene, Boehringer and Pfizer as well as speaker fees and advisory board honoraria from Janssen outside the submitted work. M.T. received research grants from Bristol-Myers Squibb, Astrazeneca, Roche and Takeda outside the submitted work. T.E. received grants from Ruprecht-Karls Universität Heidelberg, Herbert Kienzle Foundation and Else Kröner-Fresenius Foundation and received travel reimbursement from Bristol-Myers Squibb outside the submitted work. The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Purpose: Proton beam radiotherapy (PRT) has been demonstrated to improve neurocognitive sequelae particularly. Nevertheless, following PRT, increased rates of radiation-induced contrast enhancements (RICE) are feared. How safe and effective is PRT for IDH-mutated glioma WHO grade 2 and 3?, Methods: We analyzed 194 patients diagnosed with IDH-mutated WHO grade 2 (n = 128) and WHO grade 3 (n = 66) glioma who were treated with PRT from 2010 to 2020. Serial clinical and imaging follow-up was performed for a median of 5.1 years., Results: For WHO grade 2, 61% were astrocytoma and 39% oligodendroglioma while for WHO grade 3, 55% were astrocytoma and 45% oligodendroglioma. Median dose for IDH-mutated glioma was 54 Gy(RBE) [range 50.4-60 Gy(RBE)] for WHO grade 2 and 60 Gy(RBE) [range 54-60 Gy(RBE)] for WHO grade 3. Five year overall survival was 85% in patients with WHO grade 2 and 67% in patients with WHO grade 3 tumors. Overall RICE risk was 25%, being higher in patients with WHO grade 2 (29%) versus in patients with WHO grade 3 (17%, p = 0.13). RICE risk increased independent of tumor characteristics with older age (p = 0.017). Overall RICE was symptomatic in 31% of patients with corresponding CTCAE grades as follows: 80% grade 1, 7% grade 2, 13% grade 3, and 0% grade 3 + . Overall need for RICE-directed therapy was 35%., Conclusion: These data demonstrate the effectiveness of PRT for IDH-mutated glioma WHO grade 2 and 3. The RICE risk differs with WHO grading and is higher in older patients with IDH-mutated Glioma WHO grade 2 and 3., (© 2023. The Author(s).)

Objectives: To evaluate oral sequelae after head and neck radiotherapy (RT) when using two different types of intraoral appliances. Thermoplastic dental splints (active control) protect against backscattered radiation from dental structures. Semi-individualized, 3D-printed tissue retraction devices (TRDs, study group) additionally spare healthy tissue from irradiation., Materials and Methods: A total of 29 patients with head and neck cancer were enrolled in a randomized controlled pilot trial and allocated to receive TRDs ( n = 15) or conventional splints ( n = 14). Saliva quality and quantity (Saliva-Check, GC), taste perception (Taste strips, Burghart-Messtechnik), and oral disability (JFLS-8, OHIP-14, maximum mouth opening) were recorded before and 3 months after RT start. Radiotherapy target volume, modality, total dose, fractionation, and imaging guidance were case-dependent. To evaluate intra-group developments between baseline and follow-up, nonparametric Wilcoxon tests were performed. Mann-Whitney-U tests were applied for inter-group comparisons., Results: At follow-up, taste perception was unimpaired (median difference in the total score; TRDs: 0, control: 0). No significant changes were found regarding oral disability. Saliva quantity (stimulated flow) was significantly reduced with conventional splints (median -4 mL, p = 0.016), while it decreased insignificantly with TRDs (median -2 mL, p = 0.07). Follow-up was attended by 9/15 study group participants (control 13/14). Inter-group comparisons showed no significant differences but a tendency towards a better outcome for disability and saliva quality in the intervention group., Conclusion: Due to the small cohort size and the heterogeneity of the sample, the results must be interpreted with reservation. Further research must confirm the positive trends of TRD application. Negative side-effects of TRD application seem improbable.

Background: We aimed to demonstrate the effects of tumor treating fields (TTFields) in head and neck squamous cell carcinoma (HNSCC) cells when combined with radiotherapy (RT) and chemotherapy., Methods: Two human HNSCC cell lines (Cal27, FaDu) received five different treatments: TTFields, RT +/- TTFields and RT + simultaneous cisplatin +/- TTFields. Effects were quantified using clonogenic assays and flow cytometric analyses of DAPI, caspase-3 activation and γH2AX foci., Results: Treatment with RT + TTFields decreased the clonogenic survival as strong as treatment with RT + simultaneous cisplatin. The triple combination of RT + simultaneous cisplatin + TTFields even further decreased the clonogenic survival. Accordingly, combination of TTFields with RT or RT + simultaneous cisplatin increased cellular apoptosis and DNA double-strand breaks., Conclusion: TTFields therapy seems a promising combination partner in the multimodal treatment of locally advanced HNSCC. It could be used to intensify chemoradiotherapy or as alternative to chemotherapy., (© 2023 The Authors. Head & Neck published by Wiley Periodicals LLC.)

Neutropenia and agranulocytosis (N&A) are relatively rare, but potentially fatal adverse drug reactions (ADR). This study presents cases of N&A related to one or more antipsychotic drugs (APDs) in psychiatric inpatients. Data on APD utilization and reports of N&A caused by APDs were analyzed by using data from an observational pharmacovigilance program in German-speaking countries-Arzneimittelsicherheit in der Psychiatrie (AMSP)-from 1993 to 2016. 333,175 psychiatric inpatients were treated with APDs for schizophrenia and other indications during the observation period. A total of 124 cases of APD-induced N&A were documented, 48 of which fulfilled the criteria for agranulocytosis, corresponding to a rate of 0.37, respectively, 0.14 in 1000 inpatients treated with APDs. Neutropenia was more often detected in women, whereas there was no difference regarding sex in cases of agranulocytosis. Clozapine had the highest relative risk for inducing N&A and was imputed alone as a probable cause of N&A in 60 cases (1.57‰ of all patients exposed). Perazine showed the second highest relative risk with 8 cases and an incidence 0.52‰, followed by quetiapine (15 cases resp. 0.23‰ of all patients exposed) and olanzapine (7 cases; 0.13‰ of all patients exposed). N&A most often occurred during the first 3 months of treatment. Overall N&A are severe and potentially fatal complications that can occur during treatment with APDs. The results from this study largely agree with the currently available literature, highlighting the positive effects of alertness and established appropriate monitoring., (© 2023. The Author(s).)

Surgical therapy of osteoradionecrosis of the jaw (ORN) is challenging and requires treatment of the affected hard and soft tissue. To understand how tissue injury after irradiation influences surgical outcomes, the objective of this study was to find out whether (a) bone-related, (b) soft tissue-related, and (c) treatment-related parameters influence the surgical success of patients with ORN. A total of 175 patients (324 lesions) were included in this retrospective, single-center study. All patients were diagnosed with ORN and underwent surgical therapy. The primary outcome was complete soft tissue recovery (mucosa/skin) and the absence of symptoms 3 months after surgery. At the time of follow-up, 58% of patients (189 of 324 lesions) had intact intraoral or extraoral soft tissue. The extent of bone destruction had no effect on treatment success, whereas soft tissue injury due to fibrosis (OR: 0.344; CI 0.142-0.834; p = 0.01818) and xerostomia (OR: 0.163; CI 0.064-0.419; p = 0.00016) increased the probability of treatment failure. Soft tissue reconstruction with a microvascular graft improved therapeutic success compared to local wound closure (OR: 2.998; CI 1.371-6.555; p = 0.006). Thus, for the treatment of ORN, it is extremely important to pay attention not only to the extent of bone destruction but especially to soft tissue defects. Because the extent of soft tissue injury is a predictor for therapeutic success, it should influence the choice of surgical treatment.

Background: Due to the increasing expertise in transoral laser surgery and image-guided radiation therapy, treatment outcomes have recently improved in patients with early-stage glottic cancer. The objective of the current study was to evaluate intensity-modulated proton therapy (IMPT) as novel treatment option., Methods: A total of 15 patients with T1-2N0 glottic squamous cell carcinoma, treated between 2017 and 2020, were evaluated. Toxicity was recorded according to the Common Terminology Criteria for Adverse Events (CTCAE) v4.03., Results: The majority were T1a/b tumors (66.7%) and no patient had lymph node or distant metastases. The median total dose was 70 Gy relative biological effectiveness (RBE) (range 66-70 Gy RBE). The one- and two-year OS and metastases-free survival were 100%. One patient developed local failure and received salvage laryngectomy. No higher-grade acute or late toxicity was reported. The mean number of CTCAE grade I and II overall toxicity events per patient was 4.1 (95%-[confidence interval] CI 3.1-5.3) and 1.0 (95%-CI 0.5-1.5)., Conclusion: High-precision proton therapy of T1-2N0 glottic cancer resulted in exceptional treatment tolerability with high rates of laryngeal function preservation and promising oncological outcome. IMPT has the potential to become a standard treatment option for patients with early-stage laryngeal cancer., (© 2022. The Author(s).)

The United States' swine industry is under constant threat of foreign animal diseases, which may emerge without warning due to the globalized transportation networks moving people, animals, and products. Therefore, having disease control and elimination protocols in place prior to pathogen introduction is paramount for business continuity and economic recovery. During extraordinary circumstances, it may become necessary to depopulate large populations of animals, including swine, as a disease containment measure. Currently approved depopulation methods for swine present significant logistical challenges when scaled to large populations or performed in field conditions. In the United States, water-based foam is currently approved for poultry depopulation, and recent field studies demonstrate water-based foam is an effective depopulation alternative for swine. While effective, the speed at which water-based foam induces loss of consciousness prior to death, a major welfare consideration, has not been adequately investigated. In this study, 12 nursery pigs were terminated using water-based medium-expansion foam to quantify the time to induce loss of consciousness and ultimately brain death. Each pig was implanted with subdermal electrodes to capture electroencephalographic data, placed in a body sling, and suspended in a plastic bulk container that was subsequently filled with water-based foam. Electroencephalographic data was recorded for 15 min, during which the pigs remained immersed in the water-based foam. Conservatively, average (± SD) time to unconsciousness and brain death was 1 min, 53 s ± 36 s and 3 min, 3 s ± 56 s, respectively. The relatively rapid loss of consciousness compared to other methods limits the amount of distress and is overall a positive finding for the welfare of the pigs that might be depopulated with water-based foam. The findings of this study add additional evidence supporting the use of water-based medium-expansion foam for an emergency depopulation of swine., (© 2022. The Author(s).)

Background and Purpose: Radiation-induced contrast enhancements (RICE) are a common side effect following radiotherapy for glioma, but both diagnosis and handling are challenging. Due to the potential risks associated with RICE and its challenges in differentiating RICE from tumor progression, it is critical to better understand how RICE prognosis depends on iatrogenic influence., Materials and Methods: We identified 99 patients diagnosed with RICE who were previously treated with either photon or proton therapy for World Health Organization (WHO) grade 1-3 primary gliomas. Post-treatment brain MRI-based volumetric analysis and clinical data collection was performed at multiple time points., Results: The most common histologic subtypes were astrocytoma (50%) and oligodendroglioma (46%). In 67%, it was graded WHO grade 2 and in 86% an IDH mutation was present. RICE first occurred after 16 months (range: 1-160) in median. At initial RICE occurrence, 39% were misinterpreted as tumor progression. A tumor-specific therapy including chemotherapy or re-irradiation led to a RICE size progression in 86% and 92% of cases, respectively and RICE symptom progression in 57% and 65% of cases, respectively. A RICE-specific therapy such as corticosteroids or Bevacizumab for larger or symptomatic RICE led to a RICE size regression in 81% of cases with symptom stability or regression in 62% of cases., Conclusions: While with chemotherapy and re-irradiation a RICE progression was frequently observed, anti-edematous or anti-VEGF treatment frequently went along with a RICE regression. For RICE, correct diagnosis and treatment decisions are challenging and critical and should be made interdisciplinarily., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Using a sample of about 10^{10}  J/ψ events collected at a center-of-mass energy sqrt[s]=3.097  GeV with the BESIII detector, the electromagnetic Dalitz decays J/ψ→e^{+}e^{-}π^{+}π^{-}η^{'}, with η^{'}→γπ^{+}π^{-} and η^{'}→π^{+}π^{-}η, have been studied. The decay J/ψ→e^{+}e^{-}X(1835) is observed with a significance of 15σ, and also an e^{+}e^{-} invariant-mass dependent transition form factor of J/ψ→e^{+}e^{-}X(1835) is presented for the first time. The intermediate states X(2120) and X(2370) are also observed in the π^{+}π^{-}η^{'} invariant-mass spectrum with significances of 5.3σ and 7.3σ. The corresponding product branching fractions for J/ψ→e^{+}e^{-}X, X→π^{+}π^{-}η^{'} [X=X(1835), X(2120), and X(2370)] are reported.

Background: Carbon ion radiotherapy (CIRT) yields biophysical advantages compared to photons but randomized studies for the reirradiation setting are pending. The aim of the current project was to evaluate potential clinical benefits and drawbacks of CIRT compared to volumetric modulated arc therapy (VMAT) in recurrent head and neck cancer., Methods: Dose-volume parameters and local failure patterns of CIRT compared to VMAT were evaluate in 16 patients from the randomized CARE trial on head and neck cancer reirradiation., Results: Despite an increased target dose, CIRT resulted in significantly reduced organ at risk (OAR) dose across all patients (- 8.7% Dmean). The dose-volume benefits were most pronounced in the brainstem (- 20.7% Dmax) and the optic chiasma (- 13.0% Dmax). The most frequent local failure was type E (extraneous; 50%), followed type B (peripheral; 33%) and type A (central; 17%). In one patient with type A biological and/or dosimetric failure after CIRT, mMKM dose recalculation revealed reduced target coverage., Conclusions: CIRT resulted in highly improved critical OAR sparing compared to VMAT across all head and neck cancer reirradiation scenarios despite an increased prescription dose. Local failure pattern analysis revealed further potential CIRT specific clinical benefits and potential pitfalls with regard to image-guidance and biological dose-optimization., (© 2022. The Author(s).)

Background and Purpose: Proton beam radiotherapy (PRT) is used in the treatment of low-grade glioma (LGG) to mitigate long-term sequelae. Following PRT, increased rates of radiation-induced contrast enhancements (RICE) are suspected but poorly understood., Materials and Methods: We analyzed consecutive 227 patients (42 children and 185 adults) treated with PRT (54 Gy RBE) for LGG from 2010 to 2020 and followed with serial clinical exams and magnetic resonance imaging for in median 5.6 years., Results: Tumors were graded WHO 1 in a minority (n = 22, 12%) of adults, but a majority of children (n = 29, 69%). In contrast, tumors were graded WHO 2 in the majority (n = 160, 87%) of adults and a minority of children (n = 10, 24%). Five-year overall survival following PRT was 81% in adults and 91% in children. The risk of RICE was 5-fold more frequent in adults (25%) vs. children (5%; p = 0.0043). In children and adults, RICE were symptomatic in 50% and 55% (n = 1 and 26) of cases with CTCAE grade 0 in 47% (n = 23), grade 1 in 25% (n = 12), 0% grade 2 (n = 0) and 29% grade 3 (n = 14), respectively. In adults, RICE risk was associated to WHO grading (8% in WHO grade 1 vs. 24% in WHO grade 2, p = 0.026), independent of age (p = 0.44) and irradiation dose (p = 0.005), but not independent of IDH mutational status., Conclusions: These data demonstrate effectiveness of PRT for LGG in both children and adults. The RICE risk is lower in children which are a main target group for PRT and differs with WHO grading., Competing Interests: Conflict of interest The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest for the submitted work., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Background: Molecular chaperones assist protein folding, facilitate degradation of misfolded polypeptides, and thereby maintain protein homeostasis. Impaired chaperone activity leads to defective protein quality control that is implicated in multiple skeletal muscle diseases. The heat shock protein A4 (HSPA4) acts as a co-chaperone for HSP70. Previously, we showed that Hspa4 deletion causes impaired protein homeostasis in the heart. However, its functional role in skeletal muscle has not been explored., Methods: We performed a comparative phenotypic and biochemical analyses of Hspa4 knockout (KO) mice with wild-type (WT) littermates., Results: HSPA4 is markedly upregulated in regenerating WT muscle in vivo, and in differentiated myoblasts in vitro. Hspa4-KO mice are marked by growth retardation and increased variability in body weight, accompanied by 35% mortality rates during the peri-weaning period. The surviving Hspa4-KO mice experienced progressive skeletal muscle myopathy, characterized by increased number of muscle fibers with centralized nuclei, heterogeneous myofiber size distribution, inflammatory cell infiltrates and upregulation of embryonic and perinatal myosin heavy chain transcripts. Hspa4-KO muscles demonstrated an accumulation of autophagosome-associated proteins including microtubule associated protein1 light chain 3-II (LC3-II) and p62/sequestosome accompanied by increased number of TUNEL-positive nuclei., Conclusions: Our findings underscore the indispensable role of HSPA4 in maintenance of muscle integrity through contribution in skeletal muscle autophagy and apoptosis, which might provide a novel therapeutic strategy for skeletal muscle morbidities., (© 2022. The Author(s).)

Background: Carcinomas of the lips are a relatively common malignancy of the head and neck region, accounting for roughly one quarter of all oral cavity cancers. Compared to other oral cancer sites, this location has a favorable prognosis, with 5-year survival rates between 85% and 95%. This study summarizes our institutional experience in utilizing postoperative radiation for patients with squamous cell carcinoma of the upper and/or lower lip following incomplete surgical resection or positive lymph node involvement with extracapsular extension., Methods: We retrospectively reviewed the medical records of all patients at the University Hospital of Heidelberg between 2005 and 2018 treated with postoperative radiotherapy of the upper and lower lip. Nineteen patients were identified with a median age at diagnosis of 67 years (range, 41-95 years), with 58% male and 42% female patients. Fourteen patients (73.7%) underwent neck dissection, with 5 (35.7%) found to have extracapsular extension (ECE) and positive resection margin (R1/2), 2 (14.3%) only ECE, and 7 (50.0%) with only R1/2. All patients received a median cumulative dose of 66.0 Gy (range, 60.0-70.0 Gy) in a median of 2.0 Gy per fraction (range, 1.8-2.2 Gy)., Results: Median follow-up was 5.2 years. The median progression-free survival (PFS) was 3.9 years (range, 0.2-12.4 years), local disease-free survival (LDFS) was 4 years (range, 1-12 years) and overall survival (OS) was 5.2 years (range, 0.2-12.4 years). The 5-year Kaplan-Meier estimates for OS, PFS, and LDFS were 61.4%, 85.7%, and 100.0%, respectively. At last follow-up, 13 patients (68.4%) were still alive. Although no patient developed locoregional relapse, two patients developed distant relapse at a median of 15 months after radiotherapy. There was a statistically significant improvement in OS in patients treated with higher radiotherapy doses (>60.0 Gy, p = 0.044) compared to lower radiotherapy doses. PFS was significantly improved among patients who had N0 disease, with a negative resection margin, without ECE, and who were treated with intensity-modulated radiotherapy to doses >60.0 Gy. No grade 3/4 toxicity was detected; the most common grade 1/2 toxicities included dermatitis (n = 11, 57.9%), oral mucositis (n = 8, 42.1%), and dysphagia (n = 8, 42.1%)., Conclusion: Our results demonstrate excellent local control and OS with acceptable toxicity when utilizing postoperative radiotherapy in patients with squamous cell carcinoma of the upper and lower lip, despite unfavorable characteristics (advanced T or N stage and/or ECE).

Purpose: Our purpose was to develop a mechanistic model that describes and predicts radiation response after combined DNA damage repair interference (DDRi) and particle radiation therapy., Methods and Materials: The heterogeneous dose distributions of protons and 4 He ions were implemented into the "UNIfied and VERSatile bio-response Engine" (UNIVERSE). Predictions for monoenergetic and mixed fields over clinically relevant dose and linear energy transfer range were compared with experimental in vitro survival data measured in this work as well as data available in the literature, including different cell lines and DDR interferences. Ultimately, UNIVERSE predictions were investigated in a patient plan., Results: UNIVERSE accurately predicts survival of cell lines with and without DDRi in clinical settings of ion beam therapy based only on 3 parameters derived from photon data. With increasing dose or linear energy transfer, the radiosensitizing effect of DDRi decreases, resulting in diminished relative biological effect of ion beam radiation for cells subjected to DDRi in comparison to cells that are not. Similar trends were observed in patient plan recalculations; however, this analysis also suggests that DDRi + particle radiation therapy may better preserve the therapeutic window in comparison to DDRi + photon radiation therapy., Conclusions: The presented framework represents the first mechanistic model of combined DDRi and particle radiation therapy comprehensively benchmarked in clinically relevant scenarios and a step toward more personalized treatment. It reveals potential differences between DDRi + photon radiation therapy versus DDRi + particle radiation therapy, which have not been described so far. UNIVERSE could aid in appraising the clinical viability of combined administration of radiosensitizing drugs and charged particle therapy, as well as the identification of patients with known DDR deficiencies in the tumor who might benefit from therapy with light ions, freeing limited space at heavy ion therapy centers., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Purpose: To demonstrate dosimetry benefits and report clinical outcomes of stereotactic magnetic resonance (MR)-guided online adaptive radiotherapy (SMART) of abdominopelvic lymphatic oligometastases., Patients & Methods: Prospective registry data of 26 patients with 31 oligoprogressive lymphatic metastases (1-2 lesions) who received SMART between April 2020 and April 2021 was analyzed. Prostate cancer was the most common histology (69%). Most patients (63%) had received previous abdominopelvic radiotherapy (RT). SMART was delivered in 3-7 fractions based on planning target volume (PTV) location and previous dose exposures. For SMART, the baseline plan was recalculated on daily 3D MR-imaging (predicted plan), and plan adaptation was mandatory in case of planning objective violations., Results: Plan adaptation was mostly performed due to violation of planning objectives in the predicted plan (134/140 fractions, 96%) and significantly improved plan dosimetry: (1) PTV coverage was increased (predicted: median 89%, adapted: median 95%, p < 0.001), (2) organs-at-risk (OAR) overdoses were reduced (predicted: 27/140 (19%), adapted: 1/140 (1%), p < 0.001) and (3) PTV overdoses were reduced (predicted: 21/140 (15%), adapted: 1/140 (1%), p < 0.001). After a median follow-up of 9.8 months, one patient had in-field tumor progression and twelve patients had out-field tumor progression (at 6 months: progression-free survival: 63% [46-88%], local control rate: 97% [90-100%]). Treatment was tolerated well and no grade ≥3 toxicity was reported., Conclusion: SMART improves target volume coverage and yields superior OAR protection compared to non-adaptive radiotherapy, thus representing an innovative approach to challenging cases, such as repeated radiotherapy., Competing Interests: Conflict of interest statement J. H.-R. and S. K. received speaker fees and travel reimbursement from ViewRay Inc. J. H.-R. received travel reimbursement from IntraOP Medical and Elekta Instrument AB and a grant from IntraOP Medical outside the submitted work. S.A. received grants from Accuray International Sàrl, Merck Serono GmbH and Novocure GmbH outside the submitted work. S.A. received consulting fees from Accuray International Sàrl and honoraria for lectures/presentations from Accuray International Sàrl and MSD outside the submitted work. S.A. received travel reimbursements from AstraZeneca outside the submitted work. S.A. participated on advisory boards for Sanofi Genzyme outside the submitted work. J.D. and S.A.K. received grants from View Ray Inc. S.A.K. received honoraria from IBA Dosimetry outside the submitted work. J.D. received grants from CRI–The Clinical Research Institute GmbH, Accuray Incorporated, Accuray International Sàrl, RaySearch Laboratories AB, Vision RT limited, Astellas Pharma GmbH, Astra Zeneca GmbH, Solution Akademie GmbH, Ergomed PLC Surrey Research Park, Merck Serono GmbH, Siemens Healthcare GmbH, Quintiles GmbH, Pharmaceutecal Research Associates GmbH, Boehringer Ingelheim Pharma GmbH Co, PTW-Freiburg Dr. Pychlau GmbH, Nanobiotix A.A. and IntraOP Medical outside the submitted work. T.E. received grants from Ruprecht-Karls Universität Heidelberg, Herbert Kienzle Foundation and Else Kröner-Fresenius Foundation and received travel reimbursement from Bristol-Myers Squibb outside the submitted work., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Objectives: Osteoradionecrosis (ORN) of the lower jaw is a serious late complication after radiotherapy in patients with oral cavity cancer. The aim of this study is to generate more insight into which patient- and treatment-related factors are associated with the development of ORN in oral cavity cancer patients undergoing postoperative radiotherapy., Material and Methods: Retrospective evaluation and comparison of 44 patients with ORN (event group 1) matched according to 45 patients without ORN (control group 2) who received postoperative radiotherapy of oral cavity squamous cell carcinoma at our institution between 2012 and 2020. Dosimetric factors that favor the occurrence of ORN should be detected. The cumulative occurrence rate of ORN was calculated according to the Kaplan-Meier method and analyzed by Cox regression and log-rank test., Results: The median time to develop ORN was 18 months (3-93 months) after radiotherapy. Dental status before radiotherapy (RT) treatment (HR 4.5; 1.8-11.5) and dosimetric parameters including Dmean > 45 Gy (HR 2.4; 1.0-5.7), Dmax > 60 Gy (HR 1.3; 1.1-2.8) and planning target volume (PTV) proportion > 40% intersection with the lower jaw (HR 1.1; 1.0-1.1) were significantly associated with ORN., Conclusion: The results of this retrospective study reveal that oral cavity cancer patients who underwent pre-RT dental surgery as well as dosimetric parameters using Dmax > 60 Gy, higher mean doses > 45 Gy and more than 40% PTV intersection with the lower jaw bone are independent risk factors for ORN. These findings can assist in the management of patients undergoing RT for head and neck cancer regarding ORN prevention., Clinical Relevance: Poor oral hygiene and desolate dental status as well as high radiation doses to the mandibular bone significantly increase the risk of developing osteoradionecrosis. Before irradiating a patient with oral cavity cancer, an appointment with the dentist should be made and teeth sanitized if necessary. Likewise, maximum radiation doses to the lower jaw should be minimized., (© 2022. The Author(s).)

Purpose: To explore the benefit of adaptive magnetic resonance-guided stereotactic body radiotherapy (MRgSBRT) for treatment of lung tumors in different locations with a focus on ultracentral lung tumors (ULT)., Patients & Methods: A prospective cohort of 21 patients with 23 primary and secondary lung tumors was analyzed. Tumors were located peripherally (N = 10), centrally (N = 2) and ultracentrally (N = 11, planning target volume (PTV) overlap with proximal bronchi, esophagus and/or pulmonary artery). All patients received MRgSBRT with gated dose delivery and risk-adapted fractionation. Before each fraction, the baseline plan was recalculated on the anatomy of the day (predicted plan). Plan adaptation was performed in 154/165 fractions (93.3%). Comparison of dose characteristics between predicted and adapted plans employed descriptive statistics and Bayesian linear multilevel models. The posterior distributions resulting from the Bayesian models are presented by the mean together with the corresponding 95% compatibility interval (CI)., Results: Plan adaptation decreased the proportion of fractions with violated planning objectives from 94% (predicted plans) to 17% (adapted plans). In most cases, inadequate PTV coverage was remedied (predicted: 86%, adapted: 13%), corresponding to a moderate increase of PTV coverage (mean +6.3%, 95% CI: [5.3-7.4%]) and biologically effective PTV doses (BED 10 ) (BED min : +9.0 Gy [6.7-11.3 Gy], BED mean : +1.4 Gy [0.8-2.1 Gy]). This benefit was smaller in larger tumors (-0.1%/10 cm³ PTV [-0.2 to -0.02%/10 cm³ PTV]) and ULT (-2.0% [-3.1 to -0.9%]). Occurrence of exceeded maximum doses inside the PTV (predicted: 21%, adapted: 4%) and violations of OAR constraints (predicted: 12%, adapted: 1%, OR: 0.14 [0.04-0.44]) was effectively reduced. OAR constraint violations almost exclusively occurred if the PTV had touched the corresponding OAR in the baseline plan (18/19, 95%)., Conclusion: Adaptive MRgSBRT is highly recommendable for ablative treatment of lung tumors whose PTV initially contacts a sensitive OAR, such as ULT. Here, plan adaptation protects the OAR while maintaining best-possible PTV coverage., Competing Interests: JH-R and SK received speaker fees and travel reimbursement from ViewRay Inc. JH-R received travel reimbursement from IntraOP Medical and Elekta Instrument AB and a grant from IntraOP Medical outside the submitted work. SA received grants from Accuray International Sàrl, Merck Serono GmbH and Novocure GmbH outside the submitted work. SA received consulting fees from Accuray International Sàrl and honoraria for lectures/presentations from Accuray International Sàrl and MSD outside the submitted work. SA received travel reimbursements from AstraZeneca outside the submitted work. SA participated on advisory boards for Sanofi Genzyme outside the submitted work. JD received grants from CRI—The Clinical Research Institute GmbH, View Ray Inc., Accuray Incorporated, Accuray International Sàrl, RaySearch Laboratories AB, Vision RT limited, Astellas Pharma GmbH, Astra Zeneca GmbH, Solution Akademie GmbH, Ergomed PLC Surrey Research Park, Merck Serono GmbH, Siemens Healthcare GmbH, Quintiles GmbH, Pharmaceutical Research Associates GmbH, Boehringer Ingelheim Pharma GmbH Co, PTW-Freiburg Dr. Pychlau GmbH, Nanobiotix A.A. and IntraOP Medical outside the submitted work. MT received honoraria for lectures/presentations from AbbVie, AstraZeneca, Bristol-Myers Squibb, Boehringer-Ingelheim, Celgene, Chugai, Janssen, Lilly, MSD, Novartis, Pfizer, Roche and Takeda outside the submitted work. MT received travel reimbursement from AbbVie, Amgen, AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Celgene, Chugai Pharma, Janssen, Lilly, Merck, MSD, Novartis, Pfizer, Roche and Takeda outside the submitted work. MT received research grants from Bristol-Myers Squibb, Astrazeneca, Roche and Takeda outside the submitted work. MT participated on advisory boards for AbbVie, Amgen, AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Celgene, Chugai Pharma, Janssen, Lilly, Merck, MSD, Novartis, Pfizer, Roche and Takeda outside the submitted work. TE received grants from Ruprecht-Karls Universität Heidelberg, Herbert Kienzle Foundation and Else Kröner-Fresenius Foundation and received travel reimbursement from Bristol-Myers Squibb outside the submitted work. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Regnery, Buchele, Weykamp, Pohl, Hoegen, Eichkorn, Held, Ristau, Rippke, König, Thomas, Winter, Adeberg, Debus, Klüter and Hörner-Rieber.)